There is evidence that in brain there are numerous proteinases and peptidases: some may have functions similar to that of such enzymes in other tissues (protein metabolism, enzyme regulation, tissue defense and repair); others may have functions specific for the nervous system (neuropeptide formation, inactivation, axonal flow, functional metabolism in learning and sleep). Very few peptide hydrolases have been purified from brain, and we know even less about their physiological and pathological activity. The aim of our study is to understand the role of these enzymes in brain function and malfunction. We will measure enzyme activity not only with previously characterized model substrates but also with selected peptides, pure proteins, and purified protein mixtures from brain. Our aims are to identify and purify cerebral proteinases and peptidases in order to establish their properties - their physiological substrates, bond specificity, and the factors that influence their activity, such as endocrine influences, development. We will study the enzyme composition of specific structures such as glial cells and synaptosomal preparations. Of special interest are enzymes participating in neuropeptide metabolism. In characterization and isolation of the enzymes we will make use of specific proteinase and peptidase inhibitors, some of which are available, and some we plan to develop. These inhibitors will also be used to study enzyme activity in whole brain, and to inhibit myelin protein degradation under demyelinating conditions.